Hui Lu, Huang Meng-Ke, Dai Qing-Kai, Miao Cheng-Lin, Yang Yun-Long, Liu Chen-Xi, Liu Ting, Jiang Yong-Mei
Department of Laboratory Medicine, West China Second University Hospital, and Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, China.
State Key Laboratory of Biotherapy and Cancer Center/National Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.
Clin Exp Immunol. 2025 Jan 21;219(1). doi: 10.1093/cei/uxae082.
Amlexanox (ALX) is a small-molecule drug for the treatment of inflammatory, autoimmune, metabolic, and tumor diseases. At present, there are no studies on whether ALX has a therapeutic effect on inflammatory bowel disease (IBD). In this study, we used a mouse model of dextran sulfate sodium-induced colitis to investigate the effect of ALX-targeted inhibition of TBK1 on colitis. We found that the severity of colitis in mice was correlated with TBK1 expression. Notably, although ALX inhibited the activation of the TBK1-NF-κB/TBK1-IRF3 pro-inflammatory signaling pathway, it exacerbated colitis and reduced survival in mice. The results of drug safety experiments ruled out a relationship between this exacerbating effect and drug toxicity. In addition, ELISA results showed that ALX promoted the secretion of IL-1β and IFN-α, and inhibited the production of cytokines IL-6, TNF-α, IL-10, TGF-β, and secretory IgA. Flow cytometry results further showed that ALX promoted T-cell proliferation, activation, and differentiation, and thus played a pro-inflammatory role; also, ALX inhibited the generation of dendritic cells and the polarization of macrophages to M1 type, thus exerting anti-inflammatory effect. These data suggest that the regulation of ALX on the function of different immune cells is different, so the effect on the inflammatory response is bidirectional. In conclusion, our study demonstrates that simply inhibiting TBK1 in all immune cells is not effective for the treatment of colitis. Further investigation of the anti-inflammatory mechanism of ALX on dendritic cells and macrophages may provide a new strategy for the treatment of IBD.
氨来呫诺（ALX）是一种用于治疗炎症性、自身免疫性、代谢性和肿瘤性疾病的小分子药物。目前，尚无关于ALX对炎症性肠病（IBD）是否具有治疗作用的研究。在本研究中，我们使用葡聚糖硫酸钠诱导的结肠炎小鼠模型来研究ALX靶向抑制TBK1对结肠炎的影响。我们发现小鼠结肠炎的严重程度与TBK1表达相关。值得注意的是，尽管ALX抑制了TBK1-NF-κB/TBK1-IRF3促炎信号通路的激活，但它加剧了小鼠的结肠炎并降低了存活率。药物安全性实验结果排除了这种加剧作用与药物毒性之间的关系。此外，ELISA结果显示ALX促进了IL-1β和IFN-α的分泌，并抑制了细胞因子IL-6、TNF-α、IL-10、TGF-β和分泌型IgA的产生。流式细胞术结果进一步表明，ALX促进了T细胞的增殖、激活和分化，从而发挥了促炎作用；此外，ALX抑制了树突状细胞的生成以及巨噬细胞向M1型的极化，从而发挥了抗炎作用。这些数据表明，ALX对不同免疫细胞功能的调节是不同的，因此对炎症反应的影响是双向的。总之，我们的研究表明，单纯抑制所有免疫细胞中的TBK1对结肠炎治疗无效。进一步研究ALX对树突状细胞和巨噬细胞的抗炎机制可能为IBD的治疗提供新策略。
